Background: Some hemodialysis patients require large doses of erythropoiesis-stimulating agents (ESAs) to manage anemia. These patients, termed “ESA hyporesponsive,” have been characterized using various definitions. We applied three definitions of hyporesponsiveness to a large, national cohort of hemodialysis patients to assess the impact of definition on counts and on characteristics associated with hyporesponsiveness. Methods: We studied point-prevalent hemodialysis patients on May 1, 2008, with Medicare as primary payer, who survived through December 31, 2008. Included patients received recombinant human erythropoietin (EPO) in each month, August-December. Hyporesponsiveness definitions were: above the ninetieth percentile of total monthly EPO dose; above the ninetieth percentile of total monthly EPO dose divided by weight in kg; above the ninetieth percentile of total monthly EPO dose divided by hemoglobin level. Hyporesponsiveness was further classified as chronic, acute, or other. Comorbid conditions were assessed before and concurrent with the hyporesponsive period. Results: Women, African Americans, and patients aged <40 years, with cause of renal failure other than diabetes or hypertension, or longer dialysis duration, were more likely to be hyporesponsive. Antecedent comorbid conditions most predictive of any subsequent hyporesponsiveness were congestive heart failure, peripheral vascular disease, other cardiac disease, gastrointestinal bleeding, and cancer. Concurrent comorbid conditions most strongly associated with any hyporesponsiveness were gastrointestinal bleeding and cancer. All conditions were somewhat more likely when ascertained concurrently. Comorbidity burdens were lowest for non-hyporesponsive patients. Conclusions: As associations were similar between patient characteristics and three methods of characterizing EPO hyporesponsiveness, the simplest definition using EPO dose can be used.